The present invention relates to selective reduction of pyridine ring in a biaryl system comprising a—substituted or non substituted benzene ring. This invention further relates more specifically, not exclusively, to the manufacture of methylphenidate or its derivatives or salts.
Biaryl compounds of Formula I (wherein R═CONR1R2, COOCH3, COOH; X═H, Cl, Br, OMe, NH2; R1R2═H or C1-C3 alkyl groups), specifically substituted ∝-phenyl-∝-pyridyl-2-acetic acid and its derivatives such as amide, ester are the key intermediates, in the preparation of pharmaceutical drug methylphenidate (Formula II, wherein R═COOCH3; X═H) and its acid addition salts. Methylphenidate is used for the treatment of Attention Deficit Hyperactive Disorder (ADHD). Methylphenidate is also used as central nervous system stimulant

Methylphenidate is prepared by the selective reduction of the pyridine ring of a biaryl derivative of Formula I. Methods of such reduction of Formula I are reported in prior art.
In the prior art, U.S. Pat. No. 2,507,631 describes a process according to which catalytic hydrogenation of ∝-phenyl-∝-pyridyl-2-acetic acid methyl ester was carried out in glacial acetic acid medium in presence of platinum metal catalyst at room temperature to get ∝-phenyl-∝-piperidyl-2-acetic acid methyl ester and the methyl ester was subsequently hydrolyzed to give the ∝-phenyl-∝-piperidyl-2-acetic acid.
In another prior art, U.S. Pat. No. 2,957,880, a similar process was disclosed where hydrogenation of 75 parts by weight of ∝-phenyl-∝-pyridyl-2-acetamide with hydrogen was carried out in glacial acetic acid as solvent in the presence of 1 part by weight of platinum oxide at 40° C. According to '880 patent, the reaction took 26 hours for completion. The product was isolated by evaporating acetic acid and basifying the reaction mass with aqueous NaOH. The process was exemplified for ∝-phenyl ∝-piperidyl-2-acetamide.
Further, a similar process was disclosed in Journal of Medicinal Chemistry 1981, Vol. (24), (10), 1237-1240. In the process, according to this disclosure, Erythro-dl- and threo dl-2-(4-methoxy phenyl)-2-(2′-pyridyl) acetamide hydrochloride (1.1 gm, 4.5 mmol) was dissolved in 15 ml of glacial acetic acid and 50 mg of PtO2 was added. The mixture was placed under slight positive pressure of hydrogen and stirred until the hydrogen uptake ceased. The reaction mixture was filtered and evaporated under reduced pressure to get oil, which was then further purified. The 2-(4-methoxy phenyl)-2-(2′-piperidyl) acetamide obtained was further converted to methylphenidate.
Yet another process, published in Journal of Medicinal Chemistry 1996, Vol. (39), (6), 1201-1209, teaches catalytic hydrogenation of a solution of 0.43 gm (1.7 mmole) of 3-chlorophenyl pyridyl acetamide in 15 ml of acetic acid and 0.14 gm of 5% Platinum on carbon at 30-40° C. for 10 hrs. The catalyst was removed by filtration and the solvent acetic acid was evaporated to dryness, excess concentrated hydrochloric acid was added, further evaporated to dryness to give hydrochloride of 3-chlorophenyl-2-piperidyl acetamide hydrochloride.
A major drawback of the processes described in above documents is that they all use costly catalyst such as platinum metal adsorbed on carbon or platinum oxide with a very high loading [loading means higher amounts with respect to the starting compound (II)] for the selective reduction of pyridine ring. Platinum catalysts are known for their high catalytic activity in comparison with other milder metal catalyst such as Nickel or Palladium. The order of catalytic activity is Rh>Pt>Pd>Ni. By using Pt or its oxide, Platinum oxide catalyst for hydrogenation makes the process less economical. None of these processes describe the use of other less active and less costly catalysts such as Pd or Ni. Another major drawback is the impurity generation due to reduction of the benzene ring, when using platinum metal for selective reduction of pyridine ring in presence of a benzene ring. Since platinum catalysts are known for reduction of aryl rings.
Another drawback of the prior art processes is related to the use of acetic acid as a solvent. The use of these reactive solvents as a medium for reaction is resulted in impurity generation & difficulty in isolation of the product from acetic acid. It is observed that all the prior art processes used acetic acid as solvent. The use of acetic acid is required to protonate the Nitrogen atom on the pyridine rings. The use of acetic acid in reaction as solvent also generate impurities but it goes to higher level when acetic acid is distilled to isolate the product at high temperature. The product as such is difficult to isolate from the acetic acid solution because of solubility problems and makes the process and its operation less plant friendly. Since the final compound is a pharmaceutical drug, the reduction of impurities up to accepted limits also requires additional purification steps, responsible for the substantial yield losses and thereby proportional increase in the cost.
Thus there is a need in the art to discover a process with a milder and economic catalyst for the reduction of compound I and this becomes the subject of the present invention.